Aim: Ghrelin is a gastric peptide hormone in which serine 3 is acylated primarily by an n-octanoic acid and this modification is essential for ghrelin's activity. Ghrelin O-acyl transferase (GOAT) was recently discovered as the enzyme responsible for this acylation process. Ghrelin knockout (KO) studies have shown that ghrelin is implicated in learning and memory however it is not known what form of ghrelin (acyl or des-acyl ghrelin) is responsible for this effect, therefore we used male GOAT KO (GOAT -/-) and wild-type (WT) mice to investigate cognition and behavior. Methods and Results: Using the Y-maze and the novel object recognition test we showed that GOAT -/- mice exhibit spatial learning and short-term memory impairment when compared with WT mice. In addition, GOAT -/- mice are more anxious as demonstrated by the reduction in open arms entry in the elevated-plus maze task. Moreover, these mice are more anxious after an acute restraint stress when compared with WT mice in the light-dark box test. Importantly, pretreatment with acylated ghrelin (1 mg/kg) immediately before the tests, prevented the anxiety behavioral changes observed in GOAT -/- animals but is unable to reverse the memory deficit. Conclusion: Overall, our findings demonstrate that acyl-ghrelin can modulate both short-term and spatial memory, anxiety and the stress response. This data suggests that acyl-ghrelin could potentially act as a therapeutic agent in human cognitive impairment and anxiety/stress disorders.Sources of research support: Ciências sem Fronteira, NHMRC (grant number ARC FT100100966) to ZBA.